The gene that causes Juberg-Marsidi syndrome is located on the X chromosome and is called the HUWE1 gene.
When the disease is present, the HUWE1 gene has undergone a missense mutation. The missense mutation leads to one of the building blocks of protein (amino acid) to be incorrectly exchanged for another, which creates an abnormal protein. There are numerous different HUWE1 missense mutations recorded and they affect a process called protein ubiquitination. This process involves modifying numerous proteins in order to mediate a variety of cell functions. There are three main enzymes that work in protein ubiquitination; E1, E2, and E3. E3 is called ubiquitin ligase and is the final step in the process. The HUWE1 gene makes a specific E3 ubiquitin ligase. Mutations in HUWE1 may result in decreased expression of the protein and abnormal enzyme function, which could affect protein ubiquitination. Little is known about the direct relationship between specific HUWE1 mutations and the physical manifestations of the disease, but this is being studied in a mouse model.
JMS is inherited in an X-linked recessive pattern. X-linked genetic disorders are conditions caused by a non-working gene on the X chromosome and manifest mostly in males. Females that have a non-working gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes, one normal X chromosome and one X chromosome that carries the non-working gene. Males have one X chromosome that is inherited from their mother. If a male inherits an X chromosome that contains a non-working gene, he will develop the disease.
With each pregnancy, female carriers of an X-linked disorder have a 25% chance to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease, and a 25% chance to have an unaffected son.
If a male with an X-linked disorder is able to reproduce, he will pass the non-working gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.